Meningiomas, the most common primary brain tumors with a US prevalence of 170,000, arise from arachnoid cells in the three-layered membrane encompassing the central nervous system. Although histologically benign in 80% of cases, they can cause neurologic deficits by encircling and compressing critical neurovascular structures and are aggressively treated with surgery or radiation due to the lack of established medical or chemotherapies. Before January 2013, the only major known genetic contributor to meningioma formation was Neurofibromin 2 (NF2), which is disrupted by mutation or loss of chromosome 22 in about 50% of tumors. Genetic drivers for the remaining half of tumors remained undiscovered. We reported (Science, March 2013) that mutations in 5 genes and/or chromosome 22 loss underlie meningioma formation in 80% of the 300 patients studied. Mutations in 3 genes (NF2, AKT1, and SMO) have been reported in other tumor types, and 2 genes (KLF4 and TRAF7) have not had mutations associated with neoplasia. KLF4 is a transcription factor best known as one of four genes capable of inducing a pluripotent state and whose expression is decreased in several cancers, and the K409 residue makes direct DNA contact. TRAF7 is a pro- apoptotic E3 ubiquitin ligase with seven WD40 repeats in the C terminal. Approximately one-fourth of meningiomas harbor TRAF7 mutations, which commonly co-occur with recurrent AKT1E17K or recurrent KLF4K409Q mutations but are always mutually exclusive of NF2 mutations. SMO mutations, which activate Hedgehog signaling, were found in approximately 3% of meningiomas. Mutational profile predicted chromosomal instability, malignant progression, histological subtype, and anatomical location. However, the genes driving the formation of the remaining one-fifth of meningiomas remain unidentified. Specific Aims: The research proposal entails two specific aims. The first aim will build upon our preliminary meningioma classification, and use whole-exome sequencing to identify additional meningioma driver genes. To enrich for the discovery of novel meningioma genes, only tumors without mutations in known driver genes (NF2, TRAF7, AKT1, KLF4, SMO) or chromosome 22 loss will be sequenced. The second aim will characterize the impact of the recurrent KLF4K409Q mutation on DNA binding via ChIP-seq analysis and will assess the impact of this mutation on the efficiency of KLF4 to induce pluripotency. Progress on the two aims will occur simultaneously.